FDA Approves Xanomeline and Trospium Chloride (Cobenfy) for Schizophrenia

The US Food and Drug Administration has announced the approval xanomeline and trospium chloride capsules (Cobenfy), for schizophrenia.¹

With approval, xanomeline and trospium chloride capsules, formerly referred to as KarXT, is considered the first pharmacological approach to treating schizophrenia since the 1970s, following the approvals of injectable fluphenazine enanthate and fluphenazine decanoate. The approval, which makes xanomeline and trospium chloride capsules the first antipsychotic drug approved to treat schizophrenia that targets cholinergic receptors as opposed to dopamine receptors, was awarded to Bristol-Myers Squibb Company.²

“Schizophrenia is a leading cause of disability worldwide. It is a severe, chronic mental illness that is often damaging to a person’s quality of life,” said Tiffany Farchione, MD, director of the Division of Psychiatry, Office of Neuroscience in the FDA’s Center for Drug Evaluation and Research. “This drug takes the first new approach to schizophrenia treatment in decades. This approval offers a new alternative to the antipsychotic medications people with schizophrenia have previously been prescribed.”

The FDA’s decision was based on the phase 3 EMERGENT trials which demonstrated the clinical significance of xanomeline and trospium chloride capsules for positive, negative, and cognitive symptoms of schizophrenia in the short and long term.^3,4 In the EMERGENT program, 3 studies compared xanomeline and trospium chloride capsules with a placebo to test efficacy and safety and 2 evaluated the drug’s long-term safety.

A 5-week phase 3 trial found xanomeline and trospium chloride capsules significantly reduced PANSS total score compared with placebo (-20.6 vs -12.2; least squares mean difference, - 8.4; 95% confidence interval [CI], - 12.4 to -4.3; P < .001).

The open-label extension trial showed 75% of participants had ≥ 30% improvement in symptoms at 52 weeks.⁴ Back in April, the lead investigator of the EMERGENT trials, Rishi Kakar, MD, chief scientific officer and medical director at Segal Trials, told HCPLive that the drug did not stop midway through its effect.

Xanomeline and trospium chloride capsules acts as a dual M1/M4 muscarinic acetylcholine receptor agonist in the central nervous system.² Because of this, the drug affects the brain chemicals responsible for schizophrenia symptoms differently than other medications. Schizophrenia treatments typically directly regulate the dopamine receptor, but xanomeline and trospium chloride capsules only indirectly modulates.

Unlike previous schizophrenia treatments, xanomeline and trospium chloride capsules does not lead to adverse events such as weight gain, somnolence, and movement disorders.

“Due to its heterogeneous nature, schizophrenia is not a one-size-fits-all condition, and people often find themselves in a cycle of discontinuing and switching therapies,” Kakar said. “The approval of COBENFY is a transformative moment in the treatment of schizophrenia because, historically, medicines approved to treat schizophrenia have relied on the same primary pathways in the brain. By leveraging a novel pathway, COBENFY offers a new option to manage this challenging condition.”

References

1. ^{Office of the Commissioner. FDA approves drug with new mechanism of action for treatment of schizophrenia. U.S. Food and Drug Administration. September 26, 2024. Accessed September 26, 2024. https://www.fda.gov/news-events/press-announcements/fda-approves-drug-new-mechanism-action-treatment-schizophrenia.}
2. ^{Derman, C. Rishi Kakar, MD: EMERGENT Trials, FDA Accepts Xanomeline-Trospium Application. HCPLive. December 1, 2023. https://www.hcplive.com/view/rishi-kakar-md-emergent-trials-fda-accepts-xanomeline-trospium-application. Accessed September 26, 2024.}
3. ^{Derman, C. Andrew Miller, PhD: Inventor of KarXT Discusses Pivotal EMERGENT-2 Data. HCPLive. December 22, 2023. https://www.hcplive.com/view/andrew-miller-phd-inventor-of-karxt-discusses-pivotal-emergent-2-data. Accessed September 26, 2024.}
4. ^{Derman, C. Insight on the Promising 52-Week KarXT Data with Rishi Kakar, MD. HCPLive. April 17, 2024. https://www.hcplive.com/view/insight-on-the-promising-52-week-karxt-data-with-rishi-kakar-md. Accessed September 26, 2024.}
5. ^{Bristol Myers Squibb. Bristol Myers Squibb - U.S. Food and Drug Administration approves Bristol Myers Squibb’s COBENFYTM (xanomeline and Trospium Chloride), a first-in-class muscarinic agonist for the treatment of schizophrenia in adults. Bristol Myers Squibb. September 26, 2024. Accessed September 27, 2024. https://news.bms.com/news/corporate-financial/2024/U.S.-Food-and-Drug-Administration-Approves-Bristol-Myers-Squibbs-COBENFY-xanomeline-and-trospium-chloride-a-First-In-Class-Muscarinic-Agonist-for-the-Treatment-of-Schizophrenia-in-Adults/default.aspx.}